The present invention concerns a process for optical resolution of racemic 1-aryl- and 2-aryl-alkylamines including various compounds with an optically active naphthylglycolic acid. The invention also concerns a process for optical resolution of racemic 1- and 2-naphthylglycolic acid with 1-aryl- or 2-aryl-alkylamine. The invention encompasses novel diastereomeric salts, which are formed as the intermediate compounds in the process of optical resolution of 1-aryl- or 2-aryl-alkylamines, or 1- or 2-naphthylglycolic acids.
1-Aryl- and 2-aryl-alkylamines have been used as starting materials or intermediates for production of various medicines and chemicals, and further, known as resolving agents for optical resolution. Examples of such use of 1-arylalkylamines are as follows:
1-(m-Methoxyphenyl)ethylamine is used as a material for brain function improving medicine. 1-(p-Methylphenyl)ethylamine is a resolving agent for 2-hydroxyl-4-phenylbutanoic acid, which is the intermediate for angiotensin converting enzyme inhibitors such as Cilazapril, Enalapril and Benazepril and also a resolving agent for cis-permethric acid, which is a material for an insecticide. 1-(p-Chlorophenyl)ethylamine is known to be useful as a material for a bactericide in agricultural use. It is expected that use of these arylalkylamines will develop further in the future.
For the optical resolution of racemates of these amines there has been employed diastereomeric salt process, because of easy application thereof to industrial production and good reproducibility. With respect to the resolution by diastereomeric salt formation, even in the limited scope of combinations of amines and carboxylic acids, statistic data as of around 1981 shows that more than 2500 cases have been reported. [P. Newman, xe2x80x9cOptical Resolution Procedures for Chemical Compoundsxe2x80x9d, vol. 1 and 2 (1981), Optical Resolution Information Center, Manhattan College, Riverdale, N.Y.] Though such a large number of experimental results have been reported, as pointed out by Jacques et al [J. Jacques et al., xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Willy and Sons, New York, Chichester, Brisbane, Toronto (1981) p.380] and Sheldon [R. Sheldon, xe2x80x9cChirotechnology-Industrial Synthesis of Optically Active Compoundsxe2x80x9d, Marcel Dekker, Inc., New York, Basel, Hong Kong (1993) p.20], when a novel compound is; to be resolved, there is no reliable principle or theory for choosing the resolving agent, and it is inevitable to seek the resolving agent by trial and error.
Therefore, in order to resolve a racemate of this kind of amines, it has been necessary to carry out a search for a suitable resolving agent by a trial and error method, which is of course troublesome and requires a lot of time. There has been thus a strong demand, in the field of diastereomeric salt method of optical resolution, for either standards of choosing suitable resolving agents or, more specifically, acidic resolving agents which may be applied to the racemates of a wide range of amines.
The inventors resolved 1-arylalkylamines using various hydroxycarboxylic acids as the resolving agents. The results are summarized in Table 1 below. In the row of the resolving agents, the hydroxycarboxylic acids, in Table 1, xe2x80x9cAxe2x80x9d stands for mandelic acid, xe2x80x9cBxe2x80x9d for p-methylmandelic acid, xe2x80x9cCxe2x80x9d for p-methoxymandelic acid, xe2x80x9cDxe2x80x9d for 2-hydroxyphenylpropionic acid, xe2x80x9cExe2x80x9d for 2-hydroxyphenylbutanoic acid and xe2x80x9cFxe2x80x9d for 3-hydroxy-2-phenylpropionic acid. Chemical structures of these compounds are shown below. 
From the results shown in Table 1 the following was concluded:
(1) Resolving agent xe2x80x9cAxe2x80x9d resolves non-substituted and some of o- or m-substituted 1-arylalkylamines, but does not resolve p-substituted amines at all.
(2) Resolving agents xe2x80x9cBxe2x80x9d and xe2x80x9cCxe2x80x9d which have substituent at p-position resolve non-substituted, and m- and p-substituted 1-arylalkylamines with relatively high resolving efficiency. Optical purities of the products are generally low.
(3) Resolving agents xe2x80x9cDxe2x80x9d and xe2x80x9cExe2x80x9d which have one or two methylene groups in the molecules resolve non-substituted and p-substituted 1-arylalkylamines. Optical purities of the products are also low.
(4) Resolving agent xe2x80x9cFxe2x80x9d which has a hydroxy group at the xcex2-position does not resolve non-substituted 1-arylalkylamines, which are resolved by other a-hydroxycarboxylic acids.
The above conclusion can be summarized as follows: The non-substituted 1-arylalkylamines can be resolved with any of xcex1-hydroxycarboxylic acids, the o-substituted 1-arylalkylamines can be resolved with non-substituted xcex1-hydroxycarboxylic acid (resolving agent xe2x80x9cAxe2x80x9d); the m-substituted 1-arylalkylamines can be resolved with non-substituted or p-substituted xcex1-hydroxy-carboxylic acids; and p-substituted 1-arylalkylamines can be resolved with p-substituted xcex1-hydroxycarboxylic acids. On the other hand, there is no effective resolving agent for the 1-(o-, m-, p-halogen-substituted aryl)alkylamines.
Based on the above experimental results we reached the final conclusion that optical resolution can be carried out by choosing the hydroxycarboxylic acids used as the resolving agents having such molecular structures that are similar to those of 1-arylalkylamines to be resolved, in other words, by choosing a resolving agent of substantially equal molecular length to that of the substrates [K. Kinbara et al., Tetrahedron Asymmetry, 7(6),1539 (1996)] Correctness of this rule based on experience was proved by X-ray crystal structure analysis of the obtained diastereomeric salts [K. Kinbara et al., J. Chem. Soc., Perkin Trans. 2, 1996, 2615].
However, in the optical resolutions using the known substituted hydroxycarboxylic acids as the resolving agents shown in Table 1 optical purities of the products are low except for some minor cases, and therefore, it is necessary to improve the optical purities of the products by, for example, repeating recrystallization of the diastereomeric salts. This is of course a disadvantageous factor of the processes.
The inventors continued to make efforts, on the basis of the above knowledge, in finding resolving agents which may be commonly effective for optical resolution of 1-aryl- and 2-aryl-alkylamines inclusive of m- and p-substituted 1-arylalkylamines which could not have been resolved by the known technologies. As a result, the inventors discovered the facts that non-substituted and substituted 1- or 2-naphthyl-glycolic acids are useful as the novel resolving agents and that these resolving agents very efficiently resolve amines which could not have been resolved with known resolving agents or optical purities of which were low, particularly, the amine derivatives having a substituent of an alkyl group, alkyloxy group or halogen atom at m-position or p-position. It has been believed that, in optical resolution of halogen-substituted derivatives, efficient resolution could be done only when a homologous or corresponding halogen-substituted hydroxy-carboxylic acid is used as the resolving agent. The above fact that even a non-homologous resolving agent can resolve the halogen-substituted 1-aryl- or 2-aryl-alkylamines is a surprising discovery.
An object of the present invention is to utilize the above knowledge obtained by the inventors and to provide an efficient process for optical resolution of racemic 1-aryl- and 2-aryl-alkylamines in a wide range of chemical structure using novel resolving agents, optically active 1- or 2-naphthylglycolic acids.
Another object of the present invention is to provide an efficient process for optical resolution in the reversed relation of the resolving agents and the substrates to that noted above, i.e., resolution of racemic substituted or non-substituted 1- or 2-naphthylglycolic acids using an optically active 1-aryl- or 2-aryl-alkylamine as a resolving agent.
The process for preparing optically active 1-arylalkylamines according to the present invention comprises the steps of: combining racemic 1-arylalkylamine expressed by formula Ia: 
[in formula Ia, Ar stands for a substituted or non-substituted phenyl group or a substituted or non-substituted naphthyl group; having one of the following formulas 
where R3 is a C1-C5 straight or branched chain alkyl or alkyloxy group, chlorine atom, bromine atom, iodine atom or nitro group and n is zero, one, two or more; R1 stands for hydrogen atom, a C1-C5 straight or branched chain alkyl or alkyloxy group, or substituted phenyl group, the substituent of the phenyl group is a C1-C5 straight or branched chain alkyl or alkyloxy group, chlorine atom, bromine atom, iodine atom or nitro group, and may be two or more.]
with an optically active 1-naphthylglycolic acid or 2-naphthylglycolic acid, or one of their derivatives expressed by the general formula II below: 
xe2x80x83[in formula II, R2 stands for a C1-C5 straight or branched chain alkyl or alkyloxy group, chlorine atom, bromine atom, iodine atom or nitro group, and may be two or more.]
and then, decomposing the diastereomeric salt thus obtained to isolate the optically active 1-arylalkylamine.
The process for preparing an optically active 2-arylalkylamine according to the present invention comprises the steps of: combining a racemic 2-arylalkylamine expressed by formula Ib or Ic: 
[in formulas Ib and Ic, Ar and R1 have the meaning defined above.]
with an optically active 1-naphthylglycolic acid or 2-naphthylglycolic acid, or one of their derivatives, expressed by the general formula II below: 
xe2x80x83[in formula II, R2 has the meaning defined above.] and then, decomposing the diastereomeric salt thus obtained to isolate the optically active 2-arylalkylamine.
The process for preparing an optically active naphthylglycolic acid according to the present invention comprises the steps of: combining a racemate of 1-naphthylglycolic acid or 2-naphthylglycolic acid expressed by formula II: 
with an optically active 1-arylalkylamine expressed by general formula Ia or an optically active 2-arylalkylamine expressed by general formulas Ib or Ic 
[in the formulas, Ar and R1 have the meaning defined above.] and then, decomposing a diastereomeric salt thus obtained to isolate an optically active 1-naphthylglycolic acid, 2-naphthylglycolic acid or a derivative thereof.
Diastereomeric salts which are formed during the above process for preparing the optically active isomers and expressed by general formula IIIa, IIIb and IIIc: 
[In the formulas, R1 and R2 has the meaning defined above; and * indicates position of the asymmetric carbon atom.]
are novel compounds and constitute a part of the present invention.
In both the processes of the present invention, i.e,.the process where racemates of 1-aryl- or 2-aryl-alkylamines are resolved with an optically active substituted or non-substituted 1- or 2-naphthylglycolic acid as the resolving agent, and the process where racemates of substituted or non-substituted 1- or 2-naphthylglycolic acids are resolved with an optically active 1-aryl- or 2-aryl-alkylamine as the resolving agent, various solvents can be used as the reaction medium. Examples of the solvents are: a lower alcohol such as methanol, ethanol, 2-propanol, 1-propanol and 1-butanol; water; ethers; ketones such as acetone, MEK and MIBK; and a mixture of any of these solvents. Particularly, absolute alcohols and water-containing alcohols are preferable.
The resolving agents or the optically active compounds are used in such an amount that the molar ratio of the resolving agent to the substrates to be resolved is in the range of 0.2-1.2. Preferable range in molar ratio is 0.5-1.0.
In order to obtain the diastereomeric salts, in either cases where an amine is a substrate and a carboxylic acid is a resolving agent or where a carboxylic acid is a substrate and an amine is a resolving agent, both of the reactants are charged in a reaction medium and heated to a temperature of the boiling point of the medium or lower. Then, the reaction mixture is cooled down to precipitate the diastereomeric salt, which is isolated. It is preferable to seed crystals of the desired salt for the purpose of precipitating a salt of a higher optical purity. The combinations of the substrates and resolving agents according to the present invention generally give the salts of high optical purities. It is, however, of course preferable to use an appropriate quantity of the reaction medium and to cool down slowly from the temperature of the state of solution so as to avoid rapid precipitation and to cause precipitation of fully grown salt crystal. Solid/liquid separation can be carried out using an ordinary filter or a centrifuge. Rinsing the salt crystal with a suitable solvent during the separation to remove the mother liquor will give a salt of improved optical purity. The diastereomeric salt thus obtained can be refined by recrystallization from a suitable solvent to give the salt having a better optical purity.
The above diastereomeric salt may be easily subjected to double decomposition by adding an acid or an alkali, and the desired optically active compounds can be recovered. The optically active compounds will be obtained in a pure state by recrystallization in the case where an optically active naphthylglycolic acid is aimed at and distillation in the case where an optically active 1-aryl- or 2-aryl-alkylamine is targeted.
As the processes for preparing the racemates of substituted or non-substituted 1- or 2-naphthylglycolic acids, the following processes are known:
1. Bromination or chlorination of 2-acetonaphthone, the starting material, in a reaction medium to form an xcfx89-dihalide. The product is hydrolyzed, and then the reaction mixture is acidified [Schweitzer, Chem. Ber., 24 547 (1891)] This process can be carried out using 1-acetonaphthone as the starting material.
2. Reaction of naphthalene-1- or -2-aldehyde with bromoform and potassium hydroxide [Edward L. Compere Jr., J. Org. Chem., 33 2565-6 (1968)]
3. Reduction of naphthylglyoxylic acid (xcex1-oxonaphthalene acetic acid) with sodium amalgam [Bradley, Brindley, J. Chem. Soc., 1622 (1956)] or sodium borohydride.
For preparation of optically active 1- and 2-naphthylglycolic acids the following processes are known:
1. Enzymatic process using naphthalene-2-yl-oxo-acetaldehyde as the starting material [R. Howe et al., J. Med. Chem., 16, 1020 (1973)]
2. Reduction of ketocarboxylic acids in the form of a clathrate compound with xcex2-cyclophane [K. Koga et al., Chem. Pharm. Bull., 33 3571 (1985)]
3. Reduction of the same material as above under clathration by xcex2-cyclodextrine [K. Hattori et al., Bull. Chem. Soc. Jpn., 65 2690 (1992)]
None of the processes, however, are suitable for industrial practice.
The present invention enables production of optically active 1-aryl- and 2-aryl-alkylamines, which are useful as the intermediate compounds for various medicines and resolving agents for preparing the intermediates, with high efficiency or with high optical purities and high yields.
According to the invention resolution of m- or p-substituted or non-substituted 1-aryl- and 2-aryl-alkylamine will be carried out much more easily. Before, resolving agents have been chosen separately in view of the substrates to be resolved. The invention makes it possible to resolve various 1-aryl- or 2-aryl-alkylamines using only one resolving agent. Production of the optically active isomers on an industrial scale is thus facilitated.